Based on our work during past grant periods, low-frequency sonophoresis (LFS) is now clinically used, but its application is limited to only certain low-molecular weight drugs. To broaden the application of LFS, we aim to improve the treatment regimen of skin using a combination of LFS and the surfactant sodium lauryl sulfate (SLS), as well as to design nano-scale delivery vehicles to be used after LFS/SLS treatment to increase the transdermal delivery of high-molecular weight permeants, such as proteins and vaccines, to therapeutic levels. The proposed studies involve: 1) Understanding the mechanisms of heterogenous skin perturbation with LFS and the observed synergism between LFS/SLS on skin permeability enhancement. These mechanisms will be investigated by studying the cavitation field that develops in the coupling medium between the ultrasound horn and the skin. The synergistic mechanism of LFS/SLS-enhanced transdermal penetration may be identified by correlating the extent of enhanced skin permeability with the partitioning of novel fluorescent surfactants (which allow for molecular-level imaging of surfactant behavior using two-photon fluorescence microscopy) between major skin structural components. Upon determination of these mechanisms, the LFS application and topical formulation may be improved to more effectively deliver drugs through a treated skin area; 2) Promoting the formation of localized transport regions (LTRs, highly permeabilized regions that form on the surface of the skin as a result of LFS application) by controlling the nucleation of LFS-induced cavitation events, in order to reduce skin treatment areas, minimize variability between skin treatment sites, and decrease ultrasonic power input requirements; 3) Designing polymeric micelle delivery vehicles to enhance the transdermal delivery of permeants through skin pre-treated with LFS/SLS by utilizing functionalized nanoparticles (quantum dots and biomimetic gold nanoparticles) to identify optimal permeant properties for passive transdermal delivery of permeants through skin pre-treated with LFS/SLS; 4) Transport modeling of the permeant diffusion pathways through the skin, which will aid in proper clinical drug dosing by predicting the lag time to reach steady state and the steady state permeability of a drug; and 5) Investigating the safety of the LFS/SLS skin treatment by determining the reversibility of the LTRs and their biological effects. Overall, the studies proposed here aim to expand the clinical utility and efficacy of LFS/SLS as a painless and non-invasive method of transdermal drug delivery for a broad class of drugs.